Our long-term goal is to understand how inactivation of the breast cancer susceptibility gene, BRCA1, leads to breast tumorigenesis. At the cellular level, BRCA1 ensures global genome stability by coupling DNA damage-induced signals to downstream responses, including DNA damage repair and cell-cycle checkpoint activation. Because the DNA damage-induced signaling pathways that converge on BRCA1 are conserved in most cell types, BRCA1 is likely to function ubiquitously in the maintenance of genome integrity. Nonetheless, germline inactivation of BRCA1 leads principally to cancer of the breast and ovary, and the underlying basis for its tissue-restricted tumor suppressor function remains poorly defined. Recently, we discovered a novel function for BRCA1 in suppressing the ligand-independent transcriptional activity of the estrogen receptor alpha (ERalpha), a principal determinant of the growth and differentiation of breasts and ovaries. Importantly, we showed that clinically validated BRCA1 missense mutations abrogate this repression activity, suggesting that its ERalpha-specific repression function is important for the biological activity of BRCA1 in breast and ovarian tumor suppression. In human breast cancer cells, we observed an association between BRCA1 and ERalpha at endogenous estrogen-responsive gene promoters before, but not after, estrogen stimulation. Furthermore, we demonstrated that forced reduction of BRCA1 in estrogen-dependent human ovarian cancer cells could be correlated with increases in both the estrogen-independent transcription of ERalpha-target genes and estrogen-independent proliferation. We therefore hypothesize that BRCA1 represents a ligand-reversible barrier to transcriptional activation by unliganded ERalpha, and further, that mutational inactivation of BRCA1 promotes breast and ovarian epithelial cell proliferation through aberrant expression of estrogen-responsive genes. To confirm and extend this hypothesis, we propose the following aims. Aim 1 is to elucidate the mechanism by which BRCA1 represses the ligand-independent transcriptional activity of ERalpha. Aim 2 is to characterize the regulation of BRCA1-mediated ERalpha repression by both estrogen-dependent and estrogen-independent cell signals. Aim 3 is to establish the biological role of BRCA1 in the control of cellular proliferation through modulation of ligand-independent ERalpha activity. These studies should reveal novel insight into the tissue-specific tumor suppressor function of BRCA1 and provide defined molecular targets for future intervention in breast cancer.